Summary Alzheimer?s disease (AD) is a devastating neurodegenerative disorder affecting the lives of more than 5 million Americans and their families, and is the biggest forthcoming health challenge. AD is a multifactorial disorder manifested clinically by progressive memory loss, decline in cognitive functions and ultimately leading to dementia. Despite being the subject of intense research, there is no cure for AD, therefore, identifying therapies that can reduce disease progression at early stages is critical. Circadian impairment is a major feature of Alzheimer?s disease. Behavioral circadian alterations, known as sundowning, are experienced by more than 80% of patients and represent the leading factor for hospitalization and nursing home placement in AD. New research suggest that circadian disruption occurs early during disease progression and contributes to neurodegeneration, but the pathways that mediate the effects of clock dysfunction on AD pathophysiology are not well characterized yet. The proposed work will investigate the epigenome as the target of circadian deregulation. Circadian rhythms are generated by oscillation of clock genes, including BMAL1, in transcription/translation feedback loops and epigenetic mechanisms are deeply involved in their regulation. We previously reported alterations in rhythmic DNA methylation of clock genes in AD brains and identified BMAL1 as a regulator of methylation. While ample evidence demonstrates the disruption of DNA methylation in AD, the potential cross- talk between circadian dysfunction and epigenetic alterations in mediating AD pathology is yet unknown. We now propose to apply a step-wise approach starting by the identification of alterations in chromatin dynamics dictated by the circadian clock; and narrowing down to the expression of specific genes whose deregulation may trigger neurodegeneration. This work will apply cutting-edge technology to generate temporal maps of genome-wide chromatin accessibility, DNA methylation and transcription in the mouse brain in the context of circadian disruption and AD pathology. In addition, we will evaluate the mechanisms that mediate the beneficial effects of the small molecule Nobiletin (NOB) in AD mouse models, focusing on NOB activity as circadian-enhancer. These studies will define NOB targets of action in the brain and will re-evaluate their potential as disease modifying therapy. Understanding these molecular pathways may unravel novel targets and timing for improved interventions. As treatments curing or even postponing AD remain yet elusive, prolonging patient independence and daily functioning might represent a major option in clinical care.